In general, the present invention concerns microchip laboratory systems that carry out chemical and chemical-physical, physical, biochemical and/or biological processes, especially for analyzing or synthesizing substances on a substrate with a microfluid structure by controlling the movement of the substances on the substrate electronically, mechanically or in another manner. In particular, the invention concerns a supply element for such a microchip that has a first supplier to supply the substances and a second supplier to transmit the potential necessary for moving the substances corresponding to the microfluid structure.
The continuous development in this area is best illustrated by a comparison with corresponding developments in the field of microelectronics. In the field of chemical analysis as well (for example, in the areas of chromatography or electrophoresis), there is a substantial need to integrate existing stationary laboratory devices into portable systems and correspondingly miniaturize them for laboratory and clinical diagnostics. An overview of the most recent developments in this field of microchip technology is found in a collection of relevant professional publications edited by A. van den Berg and P. Bergveld and published by Kluwer Academic Publishers (Holland, 1995) with the title, Micro Total Analysis Systems. The starting point for these developments was the established method of capillary electrophoresis. Efforts had been made in the past to implement this method on a planar glass microstructure.
The basic required components for such a microchip system are shown in FIG. 1. They are basically divided into systems that have a material flow 1, and systems that represent an information flow 2 that occurs during an experiment. In the area of the material flow 1, means are necessary to supply 3 and transport 4 substances on the chip, and means are required to treat or pretreat 5 the investigated substances. Furthermore, sensors are required for detection 6 of the results of an experiment. The arising flow of information is essentially for controlling the transport of substance on the chip using, e.g., control electronics 7. In addition, a flow of information occurs while processing the signals in the signal processing step 8 of the detected measured results, and especially while evaluating or interpreting them 9. Additional needed transport steps 4′, 4″, and 4′″ are also shown.
Another motivation for corresponding miniaturization in the field of chemical analysis is to minimize the transport paths of the substances, especially between the substance supply and the respective detection point of a possibly occurring chemical reaction (see FIG. 2). It is known from the fields of liquid chromatography and electrophoresis that substances can be separated more quickly in such systems (test results are therefore available more quickly), and that individual components can be separated with a higher resolution than is possible with conventional systems. In addition, the amount of substances (especially reagents) that micro-miniaturized laboratory systems use is greatly reduced, and the substance components are mixed much more efficiently.
The above-mentioned background is discussed in detail in an article by Andreas Manz et al. on page 5 ff. of the above-cited collection. The article also states that the authors have already manufactured a microchip consisting of a layer system of individual substrates that permits a three-dimensional transport of substances.
In contrast to creating a micro-laboratory system on a glass substrate, systems are mentioned in the above-cited article that use a silicon-based microstructure. On this basis, apparently already-integrated enzyme reactors (e.g., for a glucose test), micro-reactors for immunoassays, and miniaturized reaction vessels for DNA quick assays using the method of polymerase chain reaction have been created.
A microchip laboratory system of the initially-cited type is also discussed in U.S. Pat. No. 5,858,195 where the relevant substances are moved by a system of connected channels integrated in a microchip. The movement of these substances in these channels can be precisely controlled using electrical fields that are applied along the transport channels. Given the highly-accurate control of substance movement that this allows as well as the very exact dosing of the moved substances, the substances can be precisely mixed or separated, and/or a chemical or physical-chemical reaction can be induced with the desired stoichiometry. In this laboratory system, the integrated channels also have numerous substance reservoirs that contain the necessary substances for chemical analysis or synthesis. These substances are also moved out of the reservoirs along the transport channels by means of electrical potential differences. The substances moved along the transport channels therefore contact different chemical or physical environments that allow the necessary chemical or chemical-physical reaction to take place between the respective substances. In particular, the prior-art substrate has one or more transport channel intersections at which these substances are mixed. By simultaneously using different electrical potentials at different substance reservoirs, the volumetric flows of the various substances through one or more intersections can be selectively controlled; a precise stoichiometric template is therefore possible based just on the applied electrical potentials.
By means of the cited micro-technology, complete chemical or biochemical experiments can be carried out using microchips tailored to the respective application. Supplying the microchip with the substances to be investigated and also the existing reagents is of decisive importance.
In handling microchips in measurement set-ups for experiments, the chip of the measuring system must be easily exchangeable, and the measuring set-up must be easily adaptable to different microchip layouts. This adaptability is related not only to the respective arrangement of the substance reservoirs but also to the high voltage necessary for moving the substances on the chip, and the corresponding application of the voltage to the microchip. For such a measuring set-up, you therefore need to run electrodes to the contact surfaces correspondingly provided on the microchip, and you need devices to supply the substances to the cited reservoirs. In particular, in the cited cases, the microchip dimensions range from a few millimeters to approximately 1 centimeter which makes the chip relatively difficult to handle.
Moving substances by high voltage is, however, only one of several variations. For example, the force or potential difference necessary to move the substances can also be created by applying a pressurized medium, preferably compressed air or another suitable gas medium, such as a rare gas. The movement of the substances can also be generated by a suitable temperature gradient where the movement is brought about by thermally expanding or compressing the respective substance.
In particular, the selection of the respective medium to provide the potential or force to move the substances on the microchip depends on the physical properties of the substances themselves. With substances that have charged particles, for example charged or ionized molecules or ions, the substances are preferably moved using electrical or electromagnetic fields of suitable strength. The paths travelled by these substances depend in particular on the field strength and how long the field is applied. In contrast, electrically uncharged substances are preferably moved using a flow medium such as compressed air. Given the very small dimensions of the transport channels in the microchip, only a relatively small volume of air is required on the level of picoliters. For substances that have a relatively large coefficient of thermal expansion, a thermal procedure may be recommendable to move them, yet only when the resulting increase in temperature does not influence the kinetics of the reaction during the experiment.
Given the potential complexity of the reactions, the number of required contact electrodes can be several hundred or even more. In addition, these substances can be moved in transport channels of any three-dimensional design, e.g., in troughs or grooves, or hollow channels that are enclosed on all sides. Hollow channels can be filled with a liquid or gelatinous buffer medium to further control or adjust the precise flow rates of these substances. The flow rates can be very precisely set by the applied electrical fields based on the movement of charged particles through such a gel.
By using a buffer gel or buffer solution, mixtures of charged molecules can be advantageously moved through the medium by an electrical field. Several electrical fields can be applied simultaneously or sequentially to separate substances or correspondingly supply the respective substances on a precise schedule, possibly with different time profiles. This procedure can be used to create complex field distribution or fields that migrate beyond the separating medium. Charged molecules that travel through gels with a greater degree of mobility than through other substances can thereby be separated from slower substances with less mobility. The precise spatial and temporal distribution of the fields can be determined by corresponding control or computer programs.
In addition, micromechanical or micro-electromechanical sensors are presently being considered for use in the cited area of microfluid technology. e.g., micromechanical valves, motors or pumps. A corresponding perspective on possible future technologies in this field is provided by a relevant article by Caliper Technologies Corporation.
When this new technology becomes accepted by the affected circle of users, the cited microchip will quickly become a mass-produced article and catch on similar to immunoassays as quick tests in the fields of laboratory diagnostics and clinical diagnostics. There is therefore a substantial need for a measuring set-up to practically handle and operate such a microchip that allows the easy and especially low-contamination or contamination-free supply of the investigated substances, possibly along with the necessary reagents for the respective experiment. There is also a need for a highly simplified method to handle the microchips to make them easy to use in the cited laboratory environment by chemistry or biology lab assistants who generally have a relatively low amount of technical skill.
This would also allow corresponding large-scale acceptance of the chip and relatively easy and quick evaluation of the measuring results. In addition to the appropriate and easy manipulation of the chip, users should have to deal as little as possible with the cited supply devices for supplying the microchips with the cited substances (and especially any required high voltage) or any other necessary technical devices.
It must be noted that the connecting elements between the supply lines of the supply devices and corresponding means of conveyance on the microchip are subject to more-or-less strong mechanical, electrical or chemical wear or corrosion, and are often strongly soiled when they are in direct contact with the substances on the microchip. Of particular significance is that the utilized substances (especially the reagents) in many of the relevant chemical experiments require an extremely high degree of purity. The slightest amount of impurities in the supply lines can substantially falsify the measurement results. In addition, a generic device should be easily and quickly convertible for measurements using microchips with different layouts.